We propose to use a mouse model to investigate risk modifiers and gain insight into secondary genetic events that influence tumorigenesis in Li-Fraumeni syndrome (LFS) families harboring mutations in p53. The heterogeneity that occurs in the tumor spectrum and latency in LFS patients with inherited mutations in p53 suggest risk modifiers at loci other than the major gene. Inbred CE/J mice, which succumb to multiple types of tumors similar to those in LFS, were crossed with the p53-null 129/Sv mouse. By this Cross, we have uncovered a genetic modifier of p53, mop1, which results in embryonic lethality. Additionally, the incidence of tumors changes in these crosses. This study should provide insight as to the variability in the cancer phenotype and age of tumor onset in the human disease. Ultimately, this project will provide me with the opportunity to enhance my understanding of genetics, statistics, and developmental biology. These fields of research will aid in my long-term goal of establishing myself as an independent scientist to study the influence of risk modifiers and secondary genetic events on tumorigenesis.